Tolerance of thymocytes to allogeneic i region determinants encountered prethymically. Evidence for expression of anti-Ia receptors by T cell precursors before their entry into the thymus

The present study has assessed whether precursor T cells express receptors specific for the recognition of allogeneic I region-encoded determinants before their entry into the thymus. Because the ability of thymocytes to proliferate in response to allogeneic stimulator cells was shown to primarily result from the recognition of allogeneic I region determinants, thymocytes must already express anti-Ia receptors. In contrast, the expression of anti- Ia receptors by functionally immature thymocyte precursors could not be directly assessed by mixed lymphocyte reaction reactivity. However, expression of anti-Ia receptors by thymocyte precursors could be assessed by their ability to be specifically tolerized by the allogeneic Ia determinants that they encountered during their differentiation. To determine whether T cell precursors could specifically recognize and be tolerized to allogeneic Ia determinants expressed prethymically, thymus- engrafted radiation bone marrow chimeras were constructed [A {arrow} A x B (Tx + A Thy)] such that strain A T cells would be differentiating within a syngeneic strain A thymus but would have been previously exposed to the allogeneic strain B Ia determinants of the irradiated A x B host. The strain A thymocytes from these experimental animals were indeed tolerant to the extrathymic allogeneic strain B Ia determinants expressed by the irradiated host. Such tolerance was not mediated by detectable suppression and was not explained by the presence intrathymically of extrathymic allogeneic Ia determinants. Thus, these results suggest that T cell precursors can be specifically tolerized entry into the thymus. In addition, the failure to detect the generation of thymocytes with specificity for the allogeneic Ia determinants of the irradiated host, which were not deleted prethymically, argues that novel anti-allo Ia receptor specificities are not generated intrathymically

Global high-resolution drought indices for 1981-2022

Droughts are among the most complex and devastating natural hazards globally. High-resolution datasets of drought metrics are essential for monitoring and quantifying the severity, duration, frequency, and spatial extent of droughts at regional and particularly local scales. However, current global drought indices are available only at a coarser spatial resolution (>50 km). To fill this gap, we developed four high-resolution (5 km) gridded drought records based on the standardized precipitation evaporation index (SPEI) covering the period 1981–2022. These multi-scale (1–48 months) SPEI indices are computed based on monthly precipitation (P) from the Climate Hazards Group InfraRed Precipitation with Station Data (CHIRPS, version 2) and Multi-Source Weighted-Ensemble Precipitation (MSWEP, version 2.8), and potential evapotranspiration (PET) from the Global Land Evaporation Amsterdam Model (GLEAM, version 3.7a) and hourly Potential Evapotranspiration (hPET). We generated four SPEI records based on all possible combinations of P and PET datasets: CHIRPS_GLEAM, CHIRPS_hPET, MSWEP_GLEAM, and MSWEP_hPET. These drought records were evaluated globally and exhibited excellent agreement with observation-based estimates of SPEI, root zone soil moisture, and vegetation health indices. The newly developed high-resolution datasets provide more detailed local information and can be used to assess drought severity for particular periods and regions and to determine global, regional, and local trends, thereby supporting the development of site-specific adaptation measures. These datasets are publicly available at the Centre for Environmental Data Analysis (CEDA; https://doi.org/10.5285/ac43da11867243a1bb414e1637802dec) (Gebrechorkos et al., 2023)

Heart rate reduction with esmolol is associated with improved arterial elastance in patients with septic shock: a prospective observational study

PURPOSE: Ventricular–arterial (V–A) decoupling decreases myocardial efficiency and is exacerbated by tachycardia that increases static arterial elastance (Ea). We thus investigated the effects of heart rate (HR) reduction on Ea in septic shock patients using the beta-blocker esmolol. We hypothesized that esmolol improves Ea by positively affecting the tone of arterial vessels and their responsiveness to HR-related changes in stroke volume (SV). METHODS: After at least 24 h of hemodynamic optimization, 45 septic shock patients, with an HR ≥95 bpm and requiring norepinephrine to maintain mean arterial pressure (MAP) ≥65 mmHg, received a titrated esmolol infusion to maintain HR between 80 and 94 bpm. Ea was calculated as MAP/SV. All measurements, including data from right heart catheterization, echocardiography, arterial waveform analysis, and norepinephrine requirements, were obtained at baseline and at 4 h after commencing esmolol. RESULTS: Esmolol reduced HR in all patients and this was associated with a decrease in Ea (2.19 ± 0.77 vs. 1.72 ± 0.52 mmHg l−1), arterial dP/dtmax (1.08 ± 0.32 vs. 0.89 ± 0.29 mmHg ms−1), and a parallel increase in SV (48 ± 14 vs. 59 ± 18 ml), all p < 0.05. Cardiac output and ejection fraction remained unchanged, whereas norepinephrine requirements were reduced (0.7 ± 0.7 to 0.58 ± 0.5 µg kg−1 min−1, p < 0.05). CONCLUSIONS: HR reduction with esmolol effectively improved Ea while allowing adequate systemic perfusion in patients with severe septic shock who remained tachycardic despite standard volume resuscitation. As Ea is a major determinant of V–A coupling, its reduction may contribute to improving cardiovascular efficiency in septic shock

An approximate model for cancellous bone screw fixation

This is the author's accepted manuscript. The final published article is available from the link below. Copyright @ 2013 Taylor & Francis.This paper presents a finite element (FE) model to identify parameters that affect the performance of an improved cancellous bone screw fixation technique, and hence potentially improve fracture treatment. In cancellous bone of low apparent density, it can be difficult to achieve adequate screw fixation and hence provide stable fracture fixation that enables bone healing. Data from predictive FE models indicate that cements can have a significant potential to improve screw holding power in cancellous bone. These FE models are used to demonstrate the key parameters that determine pull-out strength in a variety of screw, bone and cement set-ups, and to compare the effectiveness of different configurations. The paper concludes that significant advantages, up to an order of magnitude, in screw pull-out strength in cancellous bone might be gained by the appropriate use of a currently approved calcium phosphate cement

Changes in Breath Trihalomethane Levels Resulting from Household Water-Use Activities

Common household water-use activities such as showering, bathing, drinking, and washing clothes or dishes are potentially important contributors to individual exposure to trihalomethanes (THMs), the major class of disinfection by-products of water treated with chlorine. Previous studies have focused on showering or bathing activities. In this study, we selected 12 common water-use activities and determined which may lead to the greatest THM exposures and result in the greatest increase in the internal dose. Seven subjects performed the various water-use activities in two residences served by water utilities with relatively high and moderate total THM levels. To maintain a consistent exposure environment, the activities, exposure times, air exchange rates, water flows, water temperatures, and extraneous THM emissions to the indoor air were carefully controlled. Water, indoor air, blood, and exhaled-breath samples were collected during each exposure session for each activity, in accordance with a strict, well-defined protocol. Although showering (for 10 min) and bathing (for 14 min), as well as machine washing of clothes and opening mechanical dishwashers at the end of the cycle, resulted in substantial increases in indoor air chloroform concentrations, only showering and bathing caused significant increases in the breath chloroform levels. In the case of bromodichloromethane (BDCM), only bathing yielded a significantly higher air level in relation to the preexposure concentration. For chloroform from showering, strong correlations were observed for indoor air and exhaled breath, blood and exhaled breath, indoor air and blood, and tap water and blood. Only water and breath, and blood and breath were significantly associated for chloroform from bathing. For BDCM, significant correlations were obtained for blood and air, and blood and water from showering. Neither dibromochloromethane nor bromoform gave measurable breath concentrations for any of the activities investigated because of their much lower tap-water concentrations. Future studies will address the effects that changes in these common water-use activities may have on exposure

Effects of a brief mindfulness-based intervention on emotional regulation and levels of mindfulness in senior students

Mindfulness-based interventions have been applied in diverse populations and achieved mental health benefits. This study examined the effects of a brief mindfulness program for emotional regulation and levels of mindfulness on senior students in Brazil. The intervention consisted of six weekly meetings attended by 30 participants. It is a pre-experimental research, with pre- and post-test comparative and correlation measurements. The preliminary results, which relied on parametrical and non-parametrical tests, revealed a reduction in total emotional regulation difficulties (p = 0.0001; r = − 0.55). Also, there was an increase in the levels of mindfulness in the subtests for both dimensions under evaluation: “Awareness” (p = 0.0001; d = 0.77) and “Acceptance” (p = 0.048; d = 0.37). By associating the amount of meditative practices performed by students with the variables, a significant positive correlation was found with the mindfulness dimension “Awareness” (rP = 0.422; p = 0.020), and there was a significant negative correlation with Difficulties in emotion regulation (rS = − 0.478; p = 0.008) and with its respective subscales “Non-acceptance” (rS = − 0.654; p = 0.0001) and “Clarity” (rS = − 0.463; p = 0.010). In conclusion, the application of a brief mindfulness-based intervention is promising in Brazilian university contexts; moreover, it can bring benefits to students, e.g., an increase in emotion regulation as well as in levels of mindfulness. We suggest that further research should use an experimental design and follow-up.info:eu-repo/semantics/publishedVersio

Is early center-based child care associated with tantrums and unmanageable behavior over time up to school entry?

Background. Existing research suggests that there is a relationship between greater exposure to center-based child care and child behavioral problems though the mechanism for the impact is unclear. However the measure used to document child care has usually been average hours, which may be particularly unreliable in the early months when fewer children are in center care. In addition individual trajectories for behavior difficulties have not been studied. Objective. The purpose of the current study was to examine whether the extent of exposure to center-based child care before two years predicted the trajectory of children’s difficult behavior (i.e., tantrums and unmanageable behavior) from 30 to 51 months controlling for child and maternal characteristics. Method. Data were drawn from UK-based Families, Children and Child Care (FCCC) study (n=1201). Individual growth models were fitted to test the relation between early center-based child care experiences and subsequent difficult behavior. Results. Children with more exposure to center-based care before two had less difficult behavior at 30 months, but more increase over time. Initial levels were predicted by higher difficult temperament and lower verbal ability. Higher difficult temperament and lower family socio-economic status predicted its change over time. Conclusion. Findings suggest that early exposure to center-based care before two years old is a risk factor for subsequent behavior problems especially when children have a longer period of exposure. A possible explanatory process is that child coping strategies to manage frustration are less well developed in a group context, especially when they lag behind in expressive language

Design effect in multicenter studies: gain or loss of power?

<p>Abstract</p> <p>Background</p> <p>In a multicenter trial, responses for subjects belonging to a common center are correlated. Such a clustering is usually assessed through the design effect, defined as a ratio of two variances. The aim of this work was to describe and understand situations where the design effect involves a gain or a loss of power.</p> <p>Methods</p> <p>We developed a design effect formula for a multicenter study aimed at testing the effect of a binary factor (which thus defines two groups) on a continuous outcome, and explored this design effect for several designs (from individually stratified randomized trials to cluster randomized trials, and for other designs such as matched pair designs or observational multicenter studies).</p> <p>Results</p> <p>The design effect depends on the intraclass correlation coefficient (ICC) (which assesses the correlation between data for two subjects from the same center) but also on a statistic <it>S</it>, which quantifies the heterogeneity of the group distributions among centers (thus the level of association between the binary factor and the center) and on the degree of global imbalance (the number of subjects are then different) between the two groups. This design effect may induce either a loss or a gain in power, depending on whether the <it>S </it>statistic is respectively higher or lower than 1.</p> <p>Conclusion</p> <p>We provided a global design effect formula applying for any multicenter study and allowing identifying factors – the ICC and the distribution of the group proportions among centers – that are associated with a gain or a loss of power in such studies.</p

Patients’ experience of recurrent/metastatic head and neck squamous cell carcinoma and their perspective on the EORTC QLQC30 and QLQ-H&amp;N35 questionnaires: a qualitative study

Abstract Background Head and neck squamous cell carcinoma (HNSCC) and its associated treatments may affect all aspects of patients’ health-related quality of life (HRQoL). Although the EORTC QLQ-H&N35 is regularly administered to patients with HNSCC, there is a paucity of studies re-assessing the conceptual relevance of this patient-reported outcome (PRO) measure from a patient perspective. Furthermore, the content validity of the EORTC QLQ-C30 has not been widely documented in patients with recurrent and/or metastatic HNSCC. The objectives of this study were to understand patients’ experiences of recurrent/metastatic HNSCC and its treatments, and to evaluate the conceptual relevance and acceptability of the EORTC QLQ-C30 and QLQ-H&N35 from a patient perspective for use in clinical trials. Methods A literature review and clinician interviews were conducted to inform in-depth semi-structured telephone interviews with US patients who had received treatment for recurrent and/or metastatic HNSCC in the preceding 12 months. Interview transcripts were analysed thematically using ATLAS.ti v7; patient quotes were coded to identify concepts and themes to develop a conceptual model of HNSCC experience. Results Fourteen patients were interviewed (71% male, aged 35–84 years). Patients reported few symptoms pre-diagnosis including neck lump/swelling (n = 7/14, 50%) and/or difficulty swallowing (n = 3/14, 21%). Treatments generally comprised surgery and chemotherapy and/or radiotherapy. A number of side effects from all treatments were reported. Numbness, difficulty speaking and pain were the most reported side effects of surgery (n = 4/8, 50%); weight loss and fatigue were the most reported side effects of chemotherapy and/or radiotherapy (n = 8/13, 61%). All side effects negatively impacted patients’ HRQoL. Patients generally found the QLQ-C30 and QLQ H&N35 content to be understandable and conceptually relevant; excessive mucous production and neuropathic symptoms were among the suggested additions. Conclusions HNSCC and its diverse symptoms and treatments have a negative impact on many aspects of patients’ lives. A number of reported symptoms including difficulty speaking and swallowing, localised pain and fatigue may be important for treatment benefit evaluation in clinical trials from a patient perspective. The QLQ-C30 and QLQ-H&N35 are generally relevant and suitable for use in clinical trials. However, some items could be amended/added to ensure conceptual comprehensiveness of these measures

Pharmacokinetics and tissue distribution of PGG–paclitaxel, a novel macromolecular formulation of paclitaxel, in nu/nu mice bearing NCI-460 lung cancer xenografts

PGG–PTX is a water-soluble formulation of paclitaxel (PTX), made by conjugating PTX to poly(l-γ-glutamylglutamine) acid (PGG) via ester bonds, that spontaneously forms a nanoparticle in aqueous environments. The purpose of this study was to compare the pharmacokinetics and tissue distribution of PTX following injection of either free PTX or PGG–PTX in mice. Both [3H]PTX and PGG–[3H]PTX were administered as an IV bolus injection to mice bearing SC NCI-H460 lung cancer xenografts at a dose of 40-mg PTX equivalents/kg. Plasma, tumor, major organs, urine, and feces were collected at intervals out to 340 h. Total taxanes, taxane extractable into ethyl acetate, and native PTX were quantified by liquid scintillation counting and HPLC. Conjugation of PTX to the PGG polymer increased plasma and tumor C max, prolonged plasma half-life and the period of accumulation in tumor, and reduced washout from tumor. In plasma injection of PGG–PTX increased total taxane AUC0–340 by 23-fold above that attained with PTX. In tumors, it increased the total taxane by a factor of 7.7, extractable taxane by 5.7, and native PTX by a factor of 3.5-fold. Conjugation delayed and reduced total urinary and fecal excretion of total taxanes. Incorporation of PTX into the PGG–PTX polymer significantly prolonged the half-life of total taxanes, extractable taxane, and native PTX in both the plasma and tumor compartments. This resulted in a large increase in the amount of active PTX delivered to the tumor. PGG–PTX is an attractive candidate for further development